Background
Vitamin D is an essential nutrient that plays a major role in skeletal health. Deficiency in vitamin D has also been linked to non-skeletal health outcomes such as growth. Stunting and poor growth among children under five years of age remain a major global challenge. Previous literature has shown that blood vitamin D level is associated with stunting and poor growth. We examined the evidence regarding vitamin D supplements and their potential effects on linear growth. We also explored other outcomes related to vitamin D status, including adverse effects.
Study characteristics
We included 187 reports representing 75 studies (12,122 participants), conducted most frequently in India, USA, and Canada, among children under five years of age. In addition, 33 studies were classified as currently being conducted (ongoing) and 21 studies as 'awaiting classification' because they did not provide enough information to be categorised as included, ongoing, or excluded. Comparisons included oral vitamin D supplementation versus placebo (dummy pill) or no intervention; higher-dose vitamin D versus lower-dose vitamin D; vitamin D plus micronutrients (vitamins or minerals or both) compared to the same micronutrients alone; and higher-dose vitamin D plus micronutrients (vitamins or minerals or both) compared to lower-dose vitamin D plus the same micronutrients. Two studies reported for-profit funding, two were categorised as mixed funding (non-profit and for-profit), five reported that they had received no funding, 26 did not disclose funding sources, and the remaining studies were supported by non-profit funding.
Key findings
Supplementation with vitamin D in comparison with placebo or no intervention probably makes little to no difference in developing hypercalciuria, probably improves length or height compared to the child's age, probably makes little to no difference in stunting, and may make little to no difference in child length or height. It is uncertain whether vitamin D in comparison with placebo or no intervention impacts the development of hypercalcaemia.
Supplementation with a higher dose of vitamin D compared to a lower dose of vitamin D may make little to no difference in length or height compared to the child's age and developing hypercalciuria, or hypercalcaemia; and we are uncertain about the effects of higher-dose vitamin D on linear growth.
Supplementation with a higher dose of vitamin D along with micronutrients (vitamins or minerals, or both) compared to a lower dose of vitamin D and the same micronutrients may make little to no difference in linear growth in children under five years of age and developing hypercalciuria, and probably makes little to no difference in developing hypercalcaemia.
Conclusions
Current evidence suggests that vitamin D probably slightly improves length/height-for-age z-score compared to placebo; however, because of the quality of the evidence, we are uncertain about the true effects of vitamin D on linear growth or adverse effects among children under five years of age compared to placebo, no intervention, or lower doses of vitamin D, with or without micronutrients.
Evidence suggests that oral vitamin D supplementation may result in little to no difference in linear growth, stunting, hypercalciuria, or hypercalcaemia, compared to placebo or no intervention, but may result in a slight increase in length/height-for-age z-score (L/HAZ). Additionally, evidence suggests that compared to lower doses of vitamin D, with or without micronutrients, vitamin D supplementation may result in little to no difference in linear growth, L/HAZ, stunting, hypercalciuria, or hypercalcaemia. Small sample sizes, substantial heterogeneity in terms of population and intervention parameters, and high risk of bias across many of the included studies limit our ability to confirm with any certainty the effects of vitamin D on our outcomes. Larger, well-designed studies of long duration (several months to years) are recommended to confirm whether or not oral vitamin D supplementation may impact linear growth in children under five years of age, among both those who are healthy and those with underlying infectious or non-communicable health conditions.
Vitamin D is a secosteroid hormone that is important for its role in calcium homeostasis to maintain skeletal health. Linear growth faltering and stunting remain pervasive indicators of poor nutrition status among infants and children under five years of age around the world, and low vitamin D status has been linked to poor growth. However, existing evidence on the effects of vitamin D supplementation on linear growth and other health outcomes among infants and children under five years of age has not been systematically reviewed.
To assess effects of oral vitamin D supplementation on linear growth and other health outcomes among infants and children under five years of age.
In December 2019, we searched CENTRAL, PubMed, Embase, 14 other electronic databases, and two trials registries. We also searched the reference lists of relevant publications for any relevant trials, and we contacted key organisations and authors to obtain information on relevant ongoing and unpublished trials.
We included randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of oral vitamin D supplementation, with or without other micronutrients, compared to no intervention, placebo, a lower dose of vitamin D, or the same micronutrients alone (and not vitamin D) in infants and children under five years of age who lived in any country.
We used standard Cochrane methodological procedures.
Out of 75 studies (187 reports; 12,122 participants) included in the qualitative analysis, 64 studies (169 reports; 10,854 participants) contributed data on our outcomes of interest for meta-analysis. A majority of included studies were conducted in India, USA, and Canada. Two studies reported for-profit funding, two were categorised as receiving mixed funding (non-profit and for-profit), five reported that they received no funding, 26 did not disclose funding sources, and the remaining studies were funded by non-profit funding. Certainty of evidence varied between high and very low across outcomes (all measured at endpoint) for each comparison.
Vitamin D supplementation versus placebo or no intervention (31 studies)
Compared to placebo or no intervention, vitamin D supplementation (at doses 200 to 2000 IU daily; or up to 300,000 IU bolus at enrolment) may make little to no difference in linear growth (measured length/height in cm) among children under five years of age (mean difference (MD) 0.66, 95% confidence interval (CI) -0.37 to 1.68; 3 studies, 240 participants; low-certainty evidence); probably improves length/height-for-age z-score (L/HAZ) (MD 0.11, 95% CI 0.001 to 0.22; 1 study, 1258 participants; moderate-certainty evidence); and probably makes little to no difference in stunting (risk ratio (RR) 0.90, 95% CI 0.80 to 1.01; 1 study, 1247 participants; moderate-certainty evidence).
In terms of adverse events, vitamin D supplementation probably makes little to no difference in developing hypercalciuria compared to placebo (RR 2.03, 95% CI 0.28 to 14.67; 2 studies, 68 participants; moderate-certainty evidence). It is uncertain whether vitamin D supplementation impacts the development of hypercalcaemia as the certainty of evidence was very low (RR 0.82, 95% CI 0.35 to 1.90; 2 studies, 367 participants).
Vitamin D supplementation (higher dose) versus vitamin D (lower dose) (34 studies)
Compared to a lower dose of vitamin D (100 to 1000 IU daily; or up to 300,000 IU bolus at enrolment), higher-dose vitamin D supplementation (200 to 6000 IU daily; or up to 600,000 IU bolus at enrolment) may have little to no effect on linear growth, but we are uncertain about this result (MD 1.00, 95% CI -2.22 to 0.21; 5 studies, 283 participants), and it may make little to no difference in L/HAZ (MD 0.40, 95% CI -0.06 to 0.86; 2 studies, 105 participants; low-certainty evidence). No studies evaluated stunting.
As regards adverse events, higher-dose vitamin D supplementation may make little to no difference in developing hypercalciuria (RR 1.16, 95% CI 1.00 to 1.35; 6 studies, 554 participants; low-certainty evidence) or in hypercalcaemia (RR 1.39, 95% CI 0.89 to 2.18; 5 studies, 986 participants; low-certainty evidence) compared to lower-dose vitamin D supplementation.
Vitamin D supplementation (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s) (9 studies)
Supplementation with a higher dose of vitamin D (400 to 2000 IU daily, or up to 300,000 IU bolus at enrolment) plus micronutrients, compared to a lower dose (200 to 2000 IU daily, or up to 90,000 IU bolus at enrolment) of vitamin D with the same micronutrients, may make little to no difference in linear growth (MD 0.60, 95% CI −3.33 to 4.53; 1 study, 25 participants; low-certainty evidence). No studies evaluated L/HAZ or stunting.
In terms of adverse events, higher-dose vitamin D supplementation with micronutrients, compared to lower-dose vitamin D with the same micronutrients, may make little to no difference in developing hypercalciuria (RR 1.00, 95% CI 0.06 to 15.48; 1 study, 86 participants; low-certainty evidence) and probably makes little to no difference in developing hypercalcaemia (RR 1.00, 95% CI 0.90, 1.11; 2 studies, 126 participants; moderate-certainty evidence).
Four studies measured hyperphosphataemia and three studies measured kidney stones, but they reported no occurrences and therefore were not included in the comparison for these outcomes.